This invention relates to a novel process of producing chirally pure xcex1-amino acids and N-sulfonyl xcex1-amino acids. Compounds of the present invention are useful for a variety of purposes, including for use in pharmaceutical compositions.
A variety of techniques have been described for production of a preferred enantiomer from xcex1-amino acids. More efficient means for producing chirally pure target compounds are needed.
In one aspect, the present invention comprises a process for preparing chirally pure S-enantiomers xcex1-amino acids.
In a further aspect, a process is provided for preparing chirally pure S-enantiomers of 2-aminoalcohols, aldehydes and oximes.
In yet another aspect, a process is provided for preparing chirally pure S-enantiomers of N-sulfonyl a-amino acids.
In a further aspect, a process is provided for preparing chirally pure N-sulfonyl 2-aminoalcohols, aldehydes and oximes.
These and other aspects of the invention will be apparent to one of skill in the art upon reading of the following detailed description of the invention.
In one aspect, the present invention is directed to a process for the preparation of chiral xcex1-amino acids.
In another aspect, the present invention provides a process for the resolution of chiral N-sulfonyl xcex1-amino acids.
Both processes of the invention produce chirally pure compounds which can be converted to suitable target compounds, including the corresponding 2-aminoalcohols or N-sulfonyl 2-aminoalcohols, aldehydes and oximes, among other desirable target compounds.
As used herein, the term xe2x80x9cchirally purexe2x80x9d refers to compounds which are in 100% S-enantiomeric form as measured by chiral high performance liquid chromatography (HPLC). Other methods of measuring chiral purity include conventional analytical methods, including specific rotation, and conventional chemical methods. However, the technique used to measure chiral purity is not a limitation on the present invention.
As used herein, the term xe2x80x9cpharmaceutically usefulxe2x80x9d refers to compounds having a desired biological effect, whether as a therapeutic, immune stimulant or suppressant, adjuvant, or vaccinal agent. Similarly, a variety of compounds which are suitable for use in non-pharmaceutical applications, e.g., a diagnostic, a marker, among others may be produced by the method of the invention. However, other pharmaceutically useful compounds may be produced by this method.
The compounds produced by the present invention and any target compounds into which they are converted can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with organic and inorganic acids such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, mallic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids, and mixtures thereof. Other salts include salts with alkali metals or alkaline earth metals, such as sodium (e.g., sodium hydroxide), potassium (e.g., potassium hydroxide), calcium or magnesium.
These salts, as well as other compounds produced by the method of the invention may be in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo. In one desirable embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, xe2x80x9cProdrugs Revisited: The xe2x80x9cAd Hocxe2x80x9d Approach as a Complement to Ligand Designxe2x80x9d, Medicinal Research Reviews, 16(3):233-241, ed., John Wiley and Sons (1996).
Both natural and unnatural xcex1-amino acids, natural and unnatural 2-aminoalcohols, and intermediates thereof, may be prepared according to the present invention. Typically, xcex1-amino acids are characterized by the formula (NH2)(CHR.)(COOH), in which R, is an aliphatic radical. The a-amino acids prepared according to the invention can be converted to N-sulfonyl xcex1-amino acids and other desired compounds. Such other desired compounds include, without limitation, the corresponding 2-aminoalcohols, aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof. Similarly, both natural and unnatural N-sulfonyl xcex1-amino acids, natural and unnatural N-sulfonyl 2-aminoalcohols, and intermediates thereof, may be prepared according to the present invention. Thus, the N-sulfonyl xcex1-amino acids described herein can be readily reduced to 2-aminoalcohols, or converted to the corresponding aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof, using techniques known to those of skill in the art.
For example, chirally pure a-amino acids produced according to the method of the invention and having the formula (R)2CH(CH2)nCH(CO2H)NH-Rxe2x80x2 can readily be converted to chirally pure 2-aminoalcohols. In another example, chirally pure N-sulfonyl xcex1-amino acids produced according to the invention and having the formula (R)2CH(CH2)nCH(CO2H)NHxe2x80x94S(O)2Rxe2x80x2 are readily converted to N-sulfonyl 2-aminoalcohols of the formula (R)2CH(CH2)nCH(CH2OH)NH2Rxe2x80x2. Suitably, in the above formulae, n is 0 to about 10; R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2cycloalkyl, CH2-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH3-phenyl; and Rxe2x80x2 is selected from among H, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, heterocycle, substituted heterocycle, phenyl, substituted phenyl, benzyl, substituted benzyl, cycloalkyl, and substituted cycloalkyl, among other suitable groups. In another example, an N-sulfonyl 2-aminoalcohol having the formula (R)2CH(CH2)nCH(CH2OH)NHxe2x80x94S(O)2-2-C4H2S-5-Cl is prepared using the method of the invention. However, the chirally pure compounds produced by the methods of the present invention are not limited by the above formulae.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms, preferably one to eight carbon atoms and, most preferably, one to six carbon atoms; as used herein, the term xe2x80x9clower alkylxe2x80x9d refers to straight- and branched-chain saturated aliphatic hydrocarbon groups having one to six carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl group with at least one carbonxe2x80x94carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl groups with at least one carbonxe2x80x94carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having from one to three substituents selected from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, substituted alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to a carbocyclic aromatic system, which may be a single ring, or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, and indane.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
The term xe2x80x9csubstituted benzylxe2x80x9d refers to a benzyl (Bn) group, having substituted on the benzene ring, one to five substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, isoquinolinyl, and tetrahydrothiopyran.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkyloxy, substituted alkyloxy, alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substituted alkylcarboxy, alkylamino, substituted alkylamino, arylthio, or substituted arylthio.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d is used herein to describe a carbon-based ring having more than 3 carbon-atoms which forms a stable ring and having from one to five substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, substituted alkylamino, arylthio, heterocyclic, substituted heterocyclic, aminoalkyl, and substituted aminoalkyl.
Where the terms xe2x80x9csubstituted alkylcycloalkylxe2x80x9d, xe2x80x9csubstituted alkylOBnxe2x80x9d, xe2x80x9csubstituted alkylpyridylxe2x80x9d, xe2x80x9csubstituted alkylfuranylxe2x80x9d, xe2x80x9csubstituted alkyl NHR7xe2x80x9d, and phenyl(substituted)alkyl, xe2x80x9csubstituted alkylOHxe2x80x9d, and xe2x80x9csubstituted alkylSR8xe2x80x9d are recited in Formula I and Formula Ia below, the substitution may occur at the alkyl group or on the corresponding base compound.
As used in the definition of the R4 group in Formula I and Ia below, an N-substituted piperidinyl group may be defined as a substituted heterocyclic group. Among particularly desirable substituents are N-alkyl-, N-aryl-, N-acyl-, and N-sulfonyl piperidinyl groups. One particularly suitable N-acyl-piperidinyl group is N-t-butyloxycarbonyl (BOC)-piperidine. However, other suitable substituents can be readily identified by one of skill in the art.
The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the O(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl can be optionally substituted. The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the O(aryl) group, where the point of attachment is through the oxygen-atom and the aryl can be optionally substituted. The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the CO(alkyl) group, where the alkyl can be optionally substituted and the point of attachment is through the carbon atom of the carbonyl group and the. The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COO(alkyl) group, where the alkyl can be optionally substituted and the point of attachment is through the carbon atom of the carboxy group. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different, and the point of attachment is on the nitrogen atom.
The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The term xe2x80x9cringxe2x80x9d structure, e.g., when R3 and R4 may form a ring structure in Formula Ia, includes a monocyclic structure, a bridged cyclo structure, and fused cyclo structures, unless the type of ring structure is otherwise specified.
The term xe2x80x9cstrong non-nucleophilic basexe2x80x9d refers to a non-nucleophilic basic reagent, which does not act as a nucleophile or bind to the reagents utilized according to the reaction. A number of non-nucleophilic bases are known in the art and include sodium hydride, potassium hydride, lithium diisopropylamide and potassium hexamethyldisilazide.
The term xe2x80x9caqueous basexe2x80x9d refers to a solution composed of, at a minimum, a base and water. A number of bases which readily dissolve in water are known in the art and include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, among others. The aqueous base solution may further contain other reagents which do not interfere with the reactions of the present invention, and include organic solvents such as tetrahydrofuran, methanol, ethanol, or hydrocarbon solvents, salts such as sodium chloride, and buffers, among others.
The term xe2x80x9caqueous acidxe2x80x9d refers to a solution composed of, at a minimum, an acid and water. The aqueous acid solution may further contain other reagents which do not interfere with the reactions of the present invention.
The term xe2x80x9cstrong acidxe2x80x9d or xe2x80x9cstrong basexe2x80x9d refers to an acid or base that is completely ionized in solution. Common strong acids include HCl, HBr, HI, HNO3, H2SO4, and HClO4. Common strong bases include hydroxides of the alkali metals (Li, Na, K, Rb, Cs) and hydroxides of the heavy alkaline earths (Ca, Sr, Ba).
The term xe2x80x9cinorganicxe2x80x9d acid or xe2x80x9cinorganicxe2x80x9d base includes acids and bases which do not contain carbon.
The term xe2x80x9corganic solventxe2x80x9d may include any carbon-containing solvent known in the art, which does not react with the reagents utilized in the reaction and includes saturated hydrocarbon solvents, unsaturated hydrocarbon solvents, including aromatic hydrocarbon solvents, alcohols, halocarbons, ethers, and acetates, among others.
The chirally pure compounds can be prepared using the methods described below. Where reference to conventional techniques is made, one of skill in the art will be able to readily select appropriate synthetic methods and reagents, which are known in the synthetic organic arts or variations of these methods by one skilled in the art. See, generally, Comprehensive Organic Synthesis, xe2x80x9cSelectivity, Strategy and Efficiency in Modern Organic Chemistryxe2x80x9d, ed., I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, xe2x80x9cThe Synthesis and Reactions of Organic Compoundsxe2x80x9d, ed. J. F. Stoddard, Pergamon Press, New York (1979).
Preparation of Chirally Pure xcex1-Amino Acids
In one aspect, the invention provides a method for preparing chirally pure xcex1-amino acids from chirally impure xcex1-amino acids. For the preparation of chirally pure xcex1-amino acids XXXXVI, a novel asymmetric variant of the Strecker xcex1-amino acid synthesis is utilized (Scheme 14; J. Org. Chem. 54:1055-1062 (1989)). In this route (Scheme I), an aldehyde XXXXVII is reacted with a cyanide salts and xcex1-methylbenzylamine or a salt thereof in a 1:1:1 molar ratio in a suitable solvent to afford the compound XXXVIII. Included among desirable cyanide salt are sodium cyanide and potassium cyanide. However, other suitable cyanide salts may be readily selected for use in the method of the invention. Preferably, the solvent is 1:1 methanol to water. Suitably, the reaction is performed for about 12 to about 24 hours, and most preferably, about 18 hours. However, longer or shorter reaction times may be readily utilized. Optionally, following this reaction, a suspension containing precipitate is formed, which is subjected to filtration and is washed (e.g., with water) to provide a powder. Compound XXXVIII is dissolved with a strong inorganic acid which is desirably cold upon combination with the compound (e.g., about 0xc2x0 C. to about 10xc2x0 C.) to provide the compound XXXXIX. Desirably, the strong inorganic acid is sulfuric acid. However, other strong inorganic acids may be readily selected. The reaction mixture is neutralized with an inorganic base and extracted with an organic solvent to compound XXXXIX. Suitably, extraction may utilize ethyl acetate or another suitable compound, and further involves drying and concentrating to provide compound XXXXIX. The hydrogenolysis reaction takes place in the presence of a suitable catalyst under pressure, e.g., Pd or RaNi under 3 atm pressure, filtering to remove the catalyst followed by concentration to remove solvent provides compound XXXXX. Compound XXXXX is then dissolved with an aqueous acid to afford the derivatives of formula XXXXVI. Where XXXXX has been dried to powder form, it is dissolved in a strong inorganic acid at high temperature to afford a salt of a chirally pure xcex1-amino acid. For example, hydrochloric acid at 100xc2x0 C. may be utilized. Alternatively, other acids and other suitable temperatures may be readily selected by one of skill in the art. Most desirably, the hydrolysis step is performed over a period of about 12 to 18 hours, or longer. In one suitable embodiment, the step is performed over 16 hours. Optionally, the resulting reaction mixture is concentrated to provide a product which consists of the amino acid salt and one equivalent of ammonium salt. In this example, the product is the amino acid hydrochloride salt and one equivalent of ammonium chloride. This product is dissolved in water to which the base, e.g., sodium hydroxide or ammonium hydroxide, is added to form a solution. 
These chirally pure a-amino acids produced according to the method of the invention can be readily utilized in the form produced, or converted to a desired target compound. For example, a chirally pure a-amino acid can be readily converted to a chirally pure 2-aminoalcohol by reducing the a-amino acid to the 2-aminoalcohol and recrystallizing the 2-aminoalcohol to afford the chirally pure 2-aminoalcohol. These and other uses for the chirally pure a-amino acids of the invention will be readily apparent to those of skill in the art from the information provided herein and that known to those of skill in the art.
In another aspect, the invention provides a scheme for resolving a chirally impure N-sulfonyl xcex1-amino acid having a xcex2-branched alkyl substituent to provide a chirally pure N-sulfonyl xcex1-amino acid. Desirably, the N-sulfonyl xcex1-amino acid is N-sulfonyl xcex2-ethylnorvaline. In another embodiment, the norvaline compound can be substituted with a compound selected from among N-sulfonyl xcex2-ethylnorvaline, N-sulfonylvaline, and N-sulfonyl xcex2-n-propylnorleucine. Alternatively, one of skill in the art may use the method of the invention with another selected N-sulfonyl a-amino acid having a xcex2-branched alkyl substituent for preparing the corresponding chirally pure compound.
Suitably, N-sulfonyl xcex2-ethylnorvaline (or another selected compound) is mixed with chirally pure ephedrine hemihydrate in ethanol at a molar ratio of 1:1. The mixture is then heated to dissolve the solids. In one embodiment, the mixture is heated to about 80xc2x0 C. However, other suitable temperatures may be readily selected. Thereafter, the mixture is cooled in order to allow a precipitate to form. This cooling step may be performed at room temperature or at reduced temperature (e.g., about 5xc2x0 C.) overnight (about 16-20 hours). The temperature and the period of the cooling step each may be adjusted upwardly or downwardly, as needed or desired. Optionally, the suspension is filtered following cooling. The salt is then recrystallized and then dissolved in a solvent and a strong aqueous acid. Suitably, the recrystallizing step is performed in boiling ethyl acetate and the recrystallized salt is separated. This may be performed using filtration or other conventional methods. Suitably, the salt is dissolved in an organic solvent and strong acid. The organic extract is washed, dried and concentrated to provide the chirally pure N-sulfonyl xcex1-amino acid. In one embodiment, the wash step is performed with a strong aqueous acid such as, for example, hydrochloric acid, and drying is performed with sodium sulfate or the like.
Suitably, these chirally pure cc-amino acids and N-sulfonyl xcex1-amino acids are useful for a variety of purposes. For example, these chirally pure cc-amino acids and N-sulfonyl xcex1-amino acids can be converted to the corresponding N-sulfonyl 2-aminoalcohols by the methods described herein.
Thus, in one embodiment the chirally pure xcex1-amino acids produced according to the present invention are useful in the synthesis of chiral N-sulfonyl a-amino acids. Suitable methods for preparation of these chiral N-sulfonyl 2-amino acids are provided herein.
The processes of the invention provide efficient route to the synthesis of chirally pure S enantiomers of a-amino acids and N-sulfonyl a-amino acids which are useful in preparing 2-aminoalcohols or N-sulfonyl 2-aminoalcohols, and intermediates thereof, which are useful for a variety of purposes.
For example, the exemplary compounds provided herein, the N-sulfonyl 2-amino acids and their corresponding alcohols, aldehydes, oximes and salts, are useful for modulating xcex1-amyloid production, which is implicated in amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer""s Disease (AD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, Down""s syndrome, among others. Thus, the compounds of Formula (I) are useful in modulating beta amyloid production in subjects at risk for, or suffering from, AD or other diseases resulting from elevated levels of beta amyloid protein in the brain. These compounds and their uses are described in more detail in co-pending U.S. patent application Ser. No. 10/014,304, filed Dec. 11, 2001, which is incorporated herein by reference. The compounds of Formula (I) include pharmaceutically acceptable salts and/or hydrates or prodrugs thereof, wherein: 
R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-piperidinyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, alkylNHR7, and substituted alkylNHR7;
with the proviso that R3 and R4 are not both hydrogen;
R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSR8, or substituted alkylSR8;
R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
or R3 and R4 may be joined to form a ring;
R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH2cycloalkyl, substituted CH2Cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9;
Q is O, NH or S;
R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl;
R6 is selected from the group consisting of hydrogen, halogen and CF3;
T is selected from the group consisting of 
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2)n (1,3)dioxane, where n is 2 to 5;
W, Y and Z are independently selected from the group consisting of C, CR10 and N, with the proviso that at least one of W, Y and Z must be C;
R10 is selected from the group consisting of hydrogen and halogen;
X is selected from the group consisting of O, S, SO2, and NR11;
R11 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl;
provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry.
The point of attachment of the W-X-Y-Z-C heterocyclic ring to the SO2 group is not a limitation of the present invention. However, in one preferred embodiment, the ring is attached to the SO2 group through a carbon-atom. However, the ring may be attached through O, S, or N heteroatoms.
The compounds of formula (I) contain one or more asymmetric carbon atoms and some of the compounds may contain one or more asymmetric (chiral) centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula (I), when the compounds of Formula (I) contain one or more chiral centers, at least one of the chiral centers is of S-stereochemistry. Most preferably, the carbon atom to which N, T, R3 and R4 are attached is of S-stereochemistry.
In one embodiment, the present invention is directed toward a process for preparing chiral S enantiomers of N-sulfonyl 2-aminoalcohols of the general formula Ia: 
wherein R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2cycloalkyl, CH2-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH3-phenyl and n is 0 to about 10.
Desirably, the compounds prepared according to the method of the invention contain at least one chiral carbon center, where R in the above-noted structures is the same. In certain desired embodiments, the R groups are methyl, ethyl, and n-propyl, and most preferably the R groups are ethyl. However, the invention further encompasses producing xcex1-amino acids and 2-aminoalcohols of the general formulae provided herein where the R groups are different. In these compounds one or more additional chiral centers may be present; however, the additional chiral centers must be optically pure and must not interfere with the production of the chirally pure xcex1-amino acids, 2-aminoalcohols, and pure S enantiomers of N-sulfonyl 2-aminoalcohols of the present invention.
In another preferred embodiment, the chiral carbon center is of S-stereochemistry which gives rise to enantiomerically pure products.
In one embodiment, the method of the invention is used to produce chirally pure xcex1-amino acids which are readily converted to the N-sulfonyl xcex1-amino acids. For example, a chirally pure xcex1-amino acids prepared according to the invention can be used to prepare a compound Formula (I). Particularly desirable compounds of Forula (I) include thiophenesulfonamides, and more desirably, 5-halo thiophenesulfonamides, and most desirably, 5-halo thiophene sulfonamides with xcex2-branches in the side chain of a primary alcohol. Thus, with respect to Formula (I), the compound produced by the invention desirably has a structure in which X is S, W is C (or CR10), Y is C (or CR10) and Z is C (or CR10), and the sulfonamide is attached to C2 of the thiophene ring. More desirably, X is S, W is C (or CR10), Y is C (or CR10), Z is C (or CR10) and R6 is a halogen. Most desirably, X is S, W is C, Y is C, Z is C, R6 is a halogen, T is C(OH)R1R2, where R1 and R2 are hydrogen, R3 is H, R4 is a lower alkyl of S-stereochemistry, and R5 is H. Other desirable compounds of Formula (I) are furansulfonamides, in which X is O, W is C, Y is C, and Z is C. In one particularly desirable embodiment, the furansulfonamides of Formula (I) are further characterized by P-branches in the side chain of a primary alcohol. Thus, with respect to Formula (I), in these compounds T is C(OH)R1R2, in which R1 and R2 are hydrogen, R3 is H, R4 is a lower alkyl of S-stereochemistry, R5 is H and R6 is halogen. In preliminary screening assays in vitro and in vivo, selected compounds of these structures have been found to have unexpectedly good beta-amyloid inhibitory activity, and in many cases, better activity than compounds of Formula (I) having other heterocycles (e.g., furans, where X is O). However, other such compounds of Formula (I) are also useful for the purposes described herein.
Additionally, other chirally pure a-amino acids and N-sulfonyl a-amino acids prepared by the invention can be converted to the desired N-sulfonyl 2-aminoalcohols, which include the compounds of Formula (I). The compounds of Formula (I) are characterized by being sulfonamides of Formula (I), which have xcex2-branches in the side chain of the primary alcohol group. Thus, with respect to Formula (I), in these compounds T is C(OH)R1R2, R1 and R2 are hydrogen, R3 is H, R4 is a lower alkyl of S-stereochemistry, and R5 is H. These and other chirally pure N-sulfonyl xcex1-amino acids can be prepared following the methods described herein.
A first method of preparation consists of reaction of a 2-aminoalcohol II with the appropriate sulfonyl halide in the presence of a base such as triethylamine (TEA) and in a suitable solvent to afford compounds of Formula III. For compounds where R2 and R1 are hydrogen, oxidation of the N-sulfonyl primary alcohol with pyridinium chlorochromate (PCC) or under Swern conditions then affords the corresponding aldehyde IV which can be reacted with Grignard reagents (RMgX, where R is an organic radical and X is a halogen) to afford the secondary alcohols V as a mixture of diastereomers which can be separated by high performance liquid chromatography (HPLC) (Scheme 2). 
A second method of preparation involves reaction of an xcex1amino acid or ester IX with the appropriate sulfonyl halide in the presence of a base such as triethylamine and in a suitable solvent to afford compounds of Formula X (Scheme 3). The intermediate N-sulfonyl ester X (Rx=H) can be converted to the corresponding primary alcohol VIII (R1=R2=H) utilizing standard methodology such as LiAlH4, B2H6 or cyanuric chloride/NaBH4. The intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can also be reduced to the corresponding primary alcohol VIII (R1=R2=H) utilizing standard methodology such as LiAlH4. Alternatively, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be converted to the aldehyde IV with DiBAL. 
Finally, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be reacted with 2 equivalents of Grignard reagent to afford the tertiary alcohols III with R1=R2. Alternatively, for tertiary alcohols III with R1 not equal to R2, the corresponding Weinreb amide (see Scheme 11) of the N-sulfonyl acid can be prepared and subsequently reacted with R1MgX and R2MgX. For compounds of formula X (Rx=H) that have an asymmetric center at the a-amino acid carbon, the pure enantiomers can be obtained by standard resolution procedures employing recrystallization of salts formed with various chiral bases.
In a variation of the second method to prepare the primary alcohols, an xcex1-amino acid or ester (or N-protected derivative thereof) VI is first converted to the corresponding primary 2-aminoalcohol VII (using the methodology outlined in the previous paragraph), which is subsequently, after deprotection (if necessary), reacted with the appropriate sulfonyl halide (Scheme 4) to afford compounds of Formula VIII. 
For preparation of compounds derived from unnatural xcex1-amino acids containing beta branching in the amino acid side chain, a method of preparation based on the work of Hruby (Tet. Lett. 38: 5135-5138 (1997)) is outlined in Scheme 5. This route entails formation of the xcex1,xcex2-unsaturated amide XII of the Evans chiral auxiliary from an xcex1, xcex2-unsaturated acid XI, followed by conjugate addition of an organocuprate, trapping of the resulting enolate anion XIII with N-bromosuccinimide (NBS), displacement of the bromide XIV with azide anion (provided by tetramethylguanidinium azide (TMGA)) to afford XV, followed by reduction to the 2-aminoalcohol and subsequent sulfonylation to afford the target compound XVI. In Schemes 2 through 5, R5 is H. 
For the preparation of N-alkylated sulfonamides VIII (R5=alkyl etc.), the sulfonamide ester XVII can be N-alkylated by either treatment with a suitable base such as potassium carbonate followed by the alkylating agent R5X or by employing Mitsunobu conditions (R5OH/DEAD, TPP). LiBH4 reduction of the N-alkylated sulfonamide ester affords the N-alkylated sulfonamide in the primary alcohol series VIII (Scheme 6). These primary alcohols VIII can be converted to the secondary alcohols V or aldehyde IV series by chemistry that has been outlined above. Alternatively, the N-alkylated sulfonamide esters, or their corresponding Weinreb amides, can be treated with Grignard reagents to afford the N-alkylated tertiary alcohols III. 
When the heterocycle attached to the sulfonamide in the above alcohols is thiophene, the corresponding sulfone derivative XIX may be obtained by oxidation of the thiophene compound XVIII with MCPBA (Scheme 7). 
An alternate preparation of sulfonamides derived from unnatural 2-aminoalcohols utilizes the Bucherer modification of the Strecker xcex1-amino acid synthesis (Scheme 8). In this route, an aldehyde XX is reacted with cyanide anion and ammonium carbonate to afford the hydantoin XXI, which is hydrolyzed to the xcex1-amino acid XXII. This compound is then reduced to XXIII and sulfonylated to afford the desired compounds of Formula XXIV. 
For sulfonamides derived from 2-aminoalcohols containing an N or 0 heteroatom in the side chain, a route has been devised starting from D-serine (Scheme 9). In this route, D-serine XXV is first sulfonylated to XXVI and subsequently converted to the ketone XXVII, which is reductively aminated to the target compounds of Formula XXVIII. 
For sulfonamides derived from 2-aminoalcohols in the secondary alcohol series with R1=H and R2=CF3 (compound XXIX), a method of preparation has been devised that is outlined in Scheme 10 starting from the aldehyde IV (prepared as in Scheme 2). 
As has been mentioned in the section concerning Scheme 2, the preparation of sulfonamides derived from 2-aminoalcohols in the secondary alcohol series V results in the formation of a diastereomeric mixture. An alternate method of preparation of these compounds that results in the production of a pure diastereomer is outlined in Scheme 11 for compounds derived from L-isoleucine. This method, which utilizes chemistry previously employed by Roux (Tetrahedron 50: 5345-5360 (1994)), consists of addition of Grignard reagents to the Weinreb amide XXX (derived from the requisite xcex1-amino acid) followed by stereo specific reduction of the ketone XXXI to afford a single diastereomeric N-protected 2-aminoalcohol XXXII. Deprotection of this compound followed by reaction with sulfonyl chlorides affords the pure diastereomeric sulfonamide secondary alcohols of Formula XXXIII. 
When the heterocycle attached to the sulfonamide in the above alcohols is thiophene, the corresponding 5-iodo and 5-fluoro-thiophene derivatives may be obtained by conversation of the 5-bromo-thiophene derivative XXXIV (obtained as in Scheme 2) to a 5-trialkyltin-thiophene intermediate XXXV which can be converted to either the 5-iodo-thiophene (XXXVII) by treatment with sodium iodide and chloramine T or the 5-fluoro-thiophene analog (XXXVI) by treatment with SELECTFLUOR(trademark) (Aldrich Chemical Co) (Scheme 12). 
Sulfonamides derived from cyclohexylglycinol substituted by alkoxy and amino groups at the 4 position of the cyclohexane ring can be prepared according to the methods described herein (Scheme 13). This route entails initial hydrogenation of 4-L-hydroxyphenylglycine XXXVIII, followed by sulfonylation, reduction of the carboxylic acid with diborane and formation of the N,O-acetonide XXXIX. The 4-hydroxy acetonide XXXIX is then O-alkylated using sodium hydride and an alkylating agent such as an alkyl or benzyl bromide. This is followed by removal of the protecting group by treatment with aqueous acid to afford the 4-ether derivatives of Formula XXXX. Alternatively, the 4-hydroxy acetonide XXXIX can be oxidized to the 4-ketone which can be reductively aminated and deprotected to afford the corresponding 4-amino analogs of Formula XXXXI. 
Where desired, oximes XXXXXIV can be derived from the corresponding aldehydes IV by standard methodology as depicted in Scheme 14. 